The corpus callosum provides a pathway for contralateral projections that leads to generalization of epileptic activity. In humans and in animal models of epilepsy, callosotomy has been successfully employed to decrease the severity and frequency of seizure activity. Virtually all of the callosal projections are excitatory onto excitatory cells. Control of synaptic strength in these projections is likely to be an important mechanism in determining the strength and generalization of seizure-related electrical activity in the cerebral cortex. For example, if callosal synapses fatigue they may lose their effectiveness in transmitting epileptiform activity. Furthermore, neuromodulator-mediated actions at synaptic terminals will likely decrease release of excitatory neurotransmiters and may reduce the spread or initiation of epileptiform activity. Little is known of the specific release mechanisms in the callosal pathway. In this proposal, the development of specific callosal connections and their neuromodulation will be examined. We will use in vitro slices of frontal and parietal cortex from rat that contain callosal fibers within the section of the slice. Whole-cell patch clamp methods will be employed to record isolated excitatory synaptic currents from visually identified infragranular pyramidal neurons. Presynaptic neuromodulatory effects of acetylcholine and norepinephrine on callosal synapses will be examined and compared to a control synapse: excitatory connections arising outside the cortex in the thalamus. The results of this study will lead to information regarding the potential role of cortico-cortical connections in the generalization of cortical electrical activity during seizures.